6α-甲基-17α-羟基-黄体酮和6α-甲基-17α-羟基-11去氧-皮质酮-21-乙酸酯的微生物羟化

6α-甲基-11-去氧-17α-羟基-皮质酮-21-乙酸酯(Ⅱ)经短刺克宁汉霉微生物转化得6β-羟基化合物(Ⅵ_a)及6β,11β-羟基化合物(Ⅶ_a)。6α-甲基-17α-羟基-黄体酮(Ⅰ)经短刺克宁汉霉菌转化亦得6β-羟基化合物(Ⅵ_b)及6β,11β-羟基化合物(Ⅶ_b)。化合物(Ⅱ)如用梨头霉转化则得11α-羟化物(Ⅲ)。Ⅶ_a、Ⅶ_b、Ⅷ_a、Ⅷ_b及Ⅺ_b的结构是通过核磁共振谱和质谱证明的。     

5α-△9(11)-16α-甲基-3β,17α,21-三羟基-孕甾烯-3β,21-双醋酸酯-20酮的微生物转化

简单节杆菌A₁及耻垢杆菌MS₁两种菌混合培养转化地塞米松中间体5α-△⁹⁽¹¹⁾-16α-甲基-3μ,17μ,21-三羟基-孕甾烯-3μ,21-双醋酸酯-20酮(Ⅲ)可得到16α-甲基-△^1.4.0(11)-孕甾烯-17α,21-双羟基-3,20双酮(Ⅳ)(65%收率)及少量的16α-甲基-△^1.4孕甾烯-9α,11α-环氧-17α,21双羟基-3,20双酮(Ⅴ)。     

5α-△9(11)-16β-甲基-3β,17α,21-三羟基-孕甾烯-3β,21-双醋酸酯-20酮和5α,17α-甲基-17β-羟基-雄甾-3酮的微生物转化

用诺卡氏菌与节杆菌混合菌种转化从蕃麻皂素制得的中间体5α-△⁹⁽¹¹⁾-16-16β-甲基-3β,17α,21三羟基孕甾烯-3β,21-双醋酸酯-20酮(Ⅰ)得50%的16β-甲基-△^1,4,9(11)-孕甾三烯-20酮(Ⅱ)和少量的16β-甲基-9,11α环氧-△¹,4孕甾二烯-20酮(Ⅲ)。另外,又用同样的混合菌种转化从剑麻皂素制得的中间体5α,17α甲基-17β羟基-雄甾-3酮(Ⅳ)得50%17α甲基-17β羟基-△^1,4-雄甾二烯-3酮(Ⅴ)。如改变培养基则得3,17β-羟基-17α-甲基-9酮基-9,10开环-1,3,5(10)雄甾三烯化合物。     

血吸虫病化学治疗的研究——ⅩⅩⅩⅣ.α-氯-β-(5-硝基-2-呋喃)丙烯酰胺类及其乙烯噁二唑类衍生物的合成

Synthesis of 35 new compounds of α-chloro-β-(5-nitro-2-furyl) acrylamides and 5-[α-chloro-β-(5-nitro-2-furyl ) vinyl]-oxadiazoles by known methods are reported. In preliminary test in mice 10 compounds were found to possess pronounced activity against Schistosomiasis japonica. Among these Ⅰ₁₂, Ⅰ₁₃, Ⅰ₁₄, Ⅰ₂₀, Ⅱ₁ and Ⅱ₈ were shown to be the most effective.     

3′(5α-3β,17β-双羟基-雄甾烷-17α)-丙酸内酯(Ⅴ)的微生物转化——螺旋内酯甾(Ⅱ)的合成

3′-(5α-3β,17β-双羟基-雄甾烷-17α)-丙酸内酯(Ⅴ)经诺卡氏菌(Nocardia sp.)转化获得6个化合物(Ⅱ和Ⅵ～Ⅹ),其中螺旋内酯甾(Ⅱ)为其主要产物(～50%)。Ⅷ～Ⅹ是尚未被鉴定的羟基化合物。化合物(Ⅴ)用诺卡氏菌在氮源贫乏的培养基中转化主要生成△⁴-3-酮化合物,而在氮源丰富的培养基中转化则主要为△^1,4-3-酮的产物。     

2β-(4′-甲基- 1′-哌嗪基)- 3α-羟基-16,17-取代-5α-雄甾烷的合成

为了寻找心血管系统药物,以表雄酮为原料,合成了7个16,17位取代的目标化合物:2β-(4’-甲基-1’-哌嗪基)-3α-羟基-5α-雄甾-17-酮、2β-(4’-甲基-1’-哌嗪基)-3α,17β-二羟基-5α-雄甾烷、2β-(4’-甲基-1’-哌嗪基)-3α-羟基-16α-溴-5α-雄甾-17-酮、2β-(4’-甲基-1’-哌嗪基)-3α,16α-二羟基-17-氧-5α-雄甾烷、2β-(4’-甲基-1’-哌嗪基)-3α,16α-二羟基-17-肟-5α-雄甾烷、2β-(4’-甲基-1’-哌嗪基)-3α,16α-二羟基-17β-氨基-5α-雄甾烷和2β—(4’-甲基-1’-哌嗪基)-3α,17β-二羟基-16β-氨基-5α-雄甾烷。初步药理试验结果表明它们都有不同程度的抗心律失常活性。     

蛔蒿中α-山道年和β-山道年的薄层分离及光密度法定量

Two forms of santonin exist in Artemisia cina Berg, i. e, α-and β-santonin. α-Santonin is therapeutically effective as an anthelmintic, while β-santonin is very weakly effective, so a method for the separation and determination of both forms is required. In the present paper, separation is made on silica gel-aluminum oxide G layer and determination is performed with a Shimadzu Chromatogram Scanner Model CS-900.Weigh accurately 0.20g of Artemisia powder (60 mesh) into a 50 ml Erlenmeyer flask, add 0.10g of Ca(OH)₂ and 10.0 ml of water, then weigh the flask accurately. Boil the mixture for 10 minutes, cool, and weigh again, add more water to compensate the weight loss on boiling. Filter, apply the filtrate onto a silica gel-aluminum oxide G layer, develop with ethanol-conc, ammonia water (8:0.3), (R_f value: α-santonin 0.45,β-santonin 0.55). Scan the spot area of α-and β-santonin with a Shimadzu Chromatogram Scanner, Model CS-900, and calculate the weight with a calibration curve. Construct caliberation curves by plotting micrograms of standard α-and β-santonin vs. spot areas, two straight lines are obtained between 1～3μg, Instrument parameters are λ_s 270 nm, λ_R 400 nm, slit 10 mm, sensitivity x l, scan speed 40 mm/min, method of scanning: reflectance.The method is simple and rapid and is more sensitive than the elution method. The recovery of α-santonin is 95%. The method has been applied to the analysis of a number of different Artemisia samples.     

慢性孵育β-淀粉样肽(25-35)对培养大鼠海马神经元外向钾电流的影响

目的　研究慢性孵育β-淀粉样肽_(25-35) (β-AP_25-35)对海马神经元上瞬时外向钾电流(I_A)和延迟整流钾电流(I_K)的影响。方法　在培养的大鼠海马神经元上用膜片钳全细胞记录钾通道电流。结果　β-AP_25-35 3μmol·L^-1 孵育细胞24h ,I_K 电流幅度增加(44.3±5.4)% ,电流密度由(30.4±6.4)pA·PF^-1 增加至(43.8±4.7)pA·PF^-1 ;β-AP_25-3510μmol·L^-1 孵育12h ,I_K 电流幅度增加(69.8±4.1) % ,电流密度增加至(51.6±7.9)pA·PF^-1,呈浓度依赖性;β-AP_25-35引起的I_K 增加对TEA 5mmol·L^-1 敏感;β-AP_25-35上调I_K 的作用主要发生在β-AP_25-355用药后48h内。β-AP_25-35对I_A无显著性影响。结论　β-AP_25-35选择性地增加海马神经元上I_K,这一作用可能与β-AP的神经毒性有关     

肿瘤的化学治疗 ⅩⅩⅢ.若干[双-(β-卤乙基)-氨基]-吲■-2-羧酸及其乙酯的合成

由5(及7)-[双-(β-羥乙基)-氨基]吲(口朶)-2-羧酸乙酯(Ⅶ_a,b)合成了5(及7)-[双-(β-氯乙基)-氨基]吲(口朶)-2-羧酸乙酯(Ⅱ_a和Ⅱ_b)、5(及7)-[双-(β-溴乙基)-氨基]-吲(口朶)-2-羧酸乙酯(Ⅱ_c和Ⅱ_d)以及5(及7)-[双-(β-碘乙基)-氨基]-吲(口朶)-2-羧酸乙酯(Ⅱ_e和Ⅱ_f)。再經水解制得其相应的羧酸(I_a-f)。此外又合成了5(及7)-乙氧羰氨基-吲(口朶)-2-羧酸乙酯(IX_a,b)和5-乙氧基-7-[双-(β-氯乙基)-氨基]-吲(口朶)-2-羧酸乙酯(Ⅶ)。化合物I_a,I_b,I_c,Ⅱ_a,Ⅱ_b,Ⅱ_c,Ⅱ_e和Ⅱ_f对組織培养Hela細胞有明显的抑制作用。化合物Ⅰ_a,Ⅰ_b,Ⅱ_a和Ⅱ_b口服时对小鼠肉瘤180有明显的抑制作用。化合物Ⅰ_e,Ⅰ_f和Ⅻ对肉瘤180具有中度的抑制作用。     

Δ16-娠烯-3β-乙酰氧基-11:20-二酮的极谱测定

A simple and rapid method for the determination of △~(16)—pregnene-3β—acetoxy — 11:20 — dione has been worked out. In an aqueous 40% iso-propanol solution of 0.1N NH₄Cl, this steroid gave a double polarographic wave which could be used for its determination. The current was measured at —1.50 v. vs. S.C.E. and was proportional to the concentration in the range of 36 to 180/μg/ml. From the experimental results, the diffusion current constant I and the diffusion coefficient D have been calculated to be 1.30 and 1.15 ×10^-6 cm²/sec. respectively. This method has been applied to the analysis of a sample; the result agreed with that obtained by the spectrophotometric method.     

Inhibition of serine proteases by steroids

Proteolysis of ¹⁴C-labeled globin, as well as the hydrolysis of the specific substrate benzoyl tyrosine ethyl ester, by purified bovine chymotrypsin was found to be inhibited by several steroid hormones. The inhibition of chymotrypsin by the steroids was of a competitive nature, with K_i values of 9.9 × 10^?5 M for triamcinolone (9-fluoro-11β, 16α,17,21-tetrahydroxy-1,4-pregnadiene-3,20-dione), 1.6 × 10^?4 M for cortisol (11β,17α,21-trihydroxypregn-4-ene-3,20-dione), 3.7 × 10^?4 M for testosterone (17β-hydroxy-4-androsten-3-one), 5.0 × 10^?4 M for dexamethasone (9-fluoro-11β,17,21-trihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione), and 1.0 × 10^?4 M for epicortisol (11α,17,21-trihydroxy-4-pregnene-3,20-dione). The activity of purified bovine trypsin on its specific substrate, TAME (tosyl arginine methyl ester), also showed a similar pattern of inhibition by steroids. Both chymotrypsin and trypsin were found to bind ³H-labeled dexamethasone and cortisol. This binding was markedly inhibited by the general protease inhibitor, PMSF (phenylmethanesulfonyl fluoride), whereas the chymotrypsin-specific inhibitor, TPCK (l-[1-tosyl-amido-2-phenyl]ethylchloromethyl ketone), inhibited only the steroid binding to chymotrypsin but not to trypsin. These observations indicate that serine proteases recognize steroid hormones in a fashion similar to the recognition of their specific substrates and that the steroids inhibit activity of these enzymes at their binding sites.     

甾体化合物 Ⅺ.Δ1-16-次甲基-11-酮基-17α-羟基副肾皮酮的合成

本文是说明用较短的新路线合成△¹-16-次甲基-11-酮基-17α-羟基副腎皮酮(Ⅵ),即在化合物I中先引进C—11酮基(Ⅲ),再破断16α,17α-氧桥,加入21-乙酰氧基及在C-1脱氢,即得目的物Ⅵ。     

7α-和7β-甲基-10β,17β-二乙酰氧基-△4-雌甾烯-3酮的抗早孕作用

7α-和7β-甲基-10β,17β-二乙酰氧基-△⁴-雌甾烯-3酮(简称7α-和7β-甲-乙氧雌酮)对小鼠抗早孕ED₅₀分别为1.6和5.5 mg/kg。7α-甲-乙氧雌酮在大鼠也有抗早孕作用并使血浆孕酮浓度降低,应用10 μg/ml浓度能抑制离体妊娠大鼠卵巢孕酮合成。7α-和7β-甲-乙氧雌酮与兔子宫胞浆雌二醇受体的相对结合亲和力(RBA)分别为10.8和1.5,与孕酮受体的RBA均<1.7α-和7β-甲-乙氧雌酮都有较弱的雌激素和抗雌激素活性。     

6α-甲基强的松龙乙酸酯的合成

6α-甲基强的松龙乙酸酯(6α-methyl prednisolone acetate)(Ⅸ,R=OCOCH_3)是几种主要的甾体皮质激素药物之一,其丁二酸酯钠盐(Ⅸ,R=OCOCH_2CH_2COONa)又可作为器官移植的抗排斥药物。该化合物在6位碳原子上有一个α-甲基。引进C_6-甲基的     

国产醋酸甲地孕酮的质量研究:6-羟基-6-甲基-17α-乙酰氧基黄体酮差向异构体的分离与鉴定

用柱层析及薄层层析对国产醋酸甲地孕酮的杂质进行了分析,共分离出7个杂质点:Ⅰ₁,Ⅰ₂,Ⅰ₃,Ⅰ₄,Ⅰ₅,Ⅰ₆,Ⅰ₇,并对其中Ⅰ₃和Ⅰ₄进行分离纯制及光谱分析,确定其结构为6β-羟基-6α-甲基-17α-乙酰氧基黄体酮及其差向异构体6α-羟基-6β-甲基-17α-乙酰氧基黄体酮。本文报道了薄层层析条件(硅胶GF₂₅₄,展开剂:醋酸乙酯-甲苯=7:3)以及光谱鉴别的依据。     

甾体激素 Ⅱ.9α-氟副肾皮质激素的新合成路线

自16α,17α-环氧孕甾-4-烯-11α-醇-3,20-二酮(Ⅰ)經对甲苯磺酰化和消去反应得到16α,17α-坏氧孕甾-4,9(11)-二烯-3,20-二酮(Ⅱ),用氫溴酸打开环氧。氫解脫溴得到孕甾-4,9(11)-二烯-17α-醇-3,20-二酮(Ⅲ),引入C₂₁-OAc得到孕甾-4,9(11)-二烯-17α,21-二醇-3,20-二酮21-醋酸脂(Ⅳ),然后按已知方法合成9α-氟-可的唑(Ⅵ).(Ⅵ)对(Ⅰ)的收率为17.4%理論。也进行了由(Ⅲ)先引入9β,11β-环氧,然后引入C₂₁-OAc以合成9α-氟可的唑的試探。     

Synthesis of [3α‐3H] 17α‐Hydroxy pregnenolone and [3α‐3H] Pregnenolone

For the first time, [3α‐³H] 17α‐hydroxy pregnenolone (1) was synthesized through a multiple step sequence. The presence of [3β‐³H] isomer in RP‐HPLC purified product was identified by tritium NMR. The [3β‐³H] isomer was then separated from [3α‐³H] 17α‐hydroxy pregnenolone with chiralPAK AD‐H column. [3α‐³H] pregnenolone (2) was synthesized from commercial available 5‐pregnen‐3,20‐dione in one step with an improved procedure.